[en] Prolactin (PRL) promotes tumor growth in various experimental models and leads to prostate hyperplasia and mammary neoplasia in PRL transgenic mice. Increasing experimental evidence argues for the involvement of autocrine PRL in this process. PRL receptor antagonists have been developed to counteract these undesired proliferative actions of PRL. However, all forms of PRL receptor antagonists obtained to date exhibit partial agonism, preventing their therapeutic use as full antagonists. In the present study, we describe the development of new human PRL antagonists devoid of agonistic properties and therefore able to act as pure antagonists. This was demonstrated using several in vitro bioassays, including highly sensitive assays able to detect extremely low levels of receptor activation. These new compounds also act as pure antagonists in vivo, as assessed by analyzing their ability to competitively inhibit PRL-triggered signaling cascades in various target tissues (liver, mammary gland, and prostate). Finally, by using transgenic mice expressing PRL specifically in the prostate, which exhibit constitutively activated signaling cascades paralleling hyperplasia, we show that these new PRL analogs are able to completely revert PRL-activated events. These second generation human PRL antagonists are good candidates to be used as inhibitors of growth-promoting actions of PRL.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Bernichtein, Sophie; INSERM Unit 584
Kayser, Christine; INSERM Unit 584
Dillner, Karin; Karolinska Institute > Department of Molecular Medicine
Moulin, Stéphanie; INSERM Unit 584
Kopchick, John J.; Ohio University > Edison Biotechnology Institute, Molecular and Cellular Biology Program, and Department of Biomedical Sciences > College of Osteopathic Medicine
Martial, Joseph ; Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie et génétique moléculaire
Norstedt, Gunnar; Karolinska Institute > Department of Molecular Medicine
Isaksson, Olle; Göteborg University > Department of Internal Medicine > Sahlgrenska University Hospital
Kelly, Paul A.; INSERM Unit 584
Goffin, Vincent; INSERM Unit 584
Language :
English
Title :
Development of pure prolactin receptor antagonists
Publication date :
2003
Journal title :
Journal of Biological Chemistry
ISSN :
0021-9258
eISSN :
1083-351X
Publisher :
American Society for Biochemistry and Molecular Biology, Baltimore, United States - Maryland
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